Cancer is typically characterized by an increase in the number of abnormal, or neoplastic, cells that proliferate to form a tumor mass. Cancer cells must acquire several traits for tumor growth and progression to occur. For example, the tumor must generate new vasculature to supply blood to nourish the tumor. This process is referred to as angiogenesis. Tumor cells also must acquire the ability to spread by invading adjacent tissue and/or metastasizing to distant sites.
Angiogenesis and tumor invasion require that the normal tissue surrounding the tumor be broken down in a process referred to as tissue remodeling. Tissue remodeling is accomplished by a host of enzymes that break down the proteins in the normal tissue barriers comprising the extracellular matrix. Among the enzymes associated with degradation of the extracellular matrix and tissue remodeling are a number of proteases. The expression of some of these proteases has been correlated with tumor progression. See, Mignatti and Rifkin Physiol. Rev. 1993, 73, 161-165.
To date, most efforts to inhibit the tissue remodeling associated with tumor progression have focused on inhibiting one class of protease, the matrix metalloproteases (MMPs). MMPs are reported to aid tumor progression by degrading the basement membrane. Two such MMPs are the type IV collagenase and stromelysin.
Recently, it has been learned that a serine protease, matriptase, plays a role in degrading the extracellular matrix during tumor progression. PCT publication numbers WO 00/53232 and WO 01/97794 describe matriptase, methods of inhibiting carcinoma progression wherein matriptase plays a role, as well as compounds useful in those methods. PCT publication number WO 02/08392 describes matriptase-like serine proteases, methods for their identification and methods for screening agents that modulate the activity of a human matriptase-like serine protease. U.S. patent publication No. 2003/0050251, describes inhibitors of matriptase and of a related serine protease, MTSP1.
Recently, a small, cyclic 14-amino acid serine protease inhibitory peptide was isolated from sunflower seeds. The peptide, termed sunflower trypsin inhibitor (SFTI-1) exhibited subnanomolar inhibitory constants (Ki) against both matriptase and cathepsin G.

STFI-1 (SEQ ID NO: 1, wherein amino acid at position 2 is arginine, amino acid at position 3 is cysteine, amino acid at position 4 is threonine, amino acid at position 5 is lysine, amino acid at position 10 is isoleucine, amino acid at position 11 is cysteine, and amino acid at position 12 is phenylalanine)
SFTI-1 also appears to be a somewhat selective inhibitor having three orders of magnitude lower inhibitory activity against elastase and thrombin than against matriptase. Moreover, SFTI-1 has no detectable effect on the activity of Factor Xa (Luckett et al. J Mol. Biol. 1999, 290, 525).
However, SFTI-1 has two drawbacks that prevent it from being an ideal therapeutic agent. First, SFTI-1 is believed to be degraded in vivo, thus diminishing its efficacy, and second, SFTI-1 exhibits insufficient selectivity over other serine proteases, such as trypsin and chymotrypsin.